The molecular analysis of tumors, such as melanoma, has benefited significantly from microarray technology that can facilitate the classification of tumors based on the differential expression of genes. The data summarized in this review describe the molecular profile of aggressive cutaneous and uveal melanoma cells as that of multiple phenotypes similar to a pluripotent, embryonic-like stem cell. A noteworthy example of the plasticity of the aggressive melanoma cell phenotype is demonstrated by the ability of these tumor cells to engage in vasculogenic mimicry and neovascularization. A review of the current evidence demonstrating important cellular and molecular determinants of melanoma vasculogenic mimicry is presented. In addition, novel signaling pathways are discussed, involving VE-cadherin, EphA2, FAK, and PI 3-kinase, which promote cell migration, invasion, and matrix remodeling. The observations summarized in this review describe some of the key molecular events that regulate the process of melanoma vasculogenic mimicry and identify new signal transduction pathways that can serve as putative targets for therapeutic intervention.